Many neurodegenerative diseases, including Alzheimer's and Parkinson's diseases, are caused by protein misfolding. Cellular proteins that adopt abnormal pathogenic conformations oligomerize and subsequently form soluble and/or insoluble aggregates in cells causing neuronal dysfunction and death. Polyglutamine (polyQ) diseases belong to the protein misfolding disease group. It is now known that polyQ toxicity is attributed to the toxic gain-of-function nature of misfolded disease proteins that harbour the expanded polyQ domain. Unfolded protein response (UPR) is one inducible cellular protective pathway that responds to the emergence of misfolded proteins in cells. It has been reported that this mechanism is involved in neurodegenerative diseases, including polyglutamine-induced neurodegeneration. UPR can be mediated by the interaction between misfolded proteins in the endoplasmic reticulum and the molecular chaperone GRP78/BiP, and this interaction would cause the activation of UPR sensors, including activating transcription factor 6 (ATF6), inositol requiring 1 (IRE1) and PKR-like endoplasmic reticulum kinase (PERK). The induction of GRP78/BiP expression has been used as a reliable indicator of UPR. Upregulation of GRP78/Bip has been observed in polyQ degeneration, which clearly indicates the involvement of protein misfolding in polyQ pathogenesis. It is likely, however, that there are other mechanisms involved in polyQ diseases. In particular, the mRNA transcripts that encode the polyQ peptides can play a role in these diseases, especially when the mRNAs encode the polyQ portion as an expanded CAG triplet nucleotide repeat. Such expanded CAG-RNAs are known to contribute to cytotoxicity through mechanisms that are independent of polyQ-mediated cytotoxicity.
Accordingly, there is a continued need to develop new and effective methods and compositions for treating polyQ diseases by reducing or eliminating cytotoxicity induced by the expanded CAG-RNA molecules. This invention fulfills this and other related needs.